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  Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design

Fedorov, R., Vasan, R., Gosh, D. K., & Schlichting, I. (2004). Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design. Proceedings of the National Academy of Sciences of the United States of America, 101(16), 5892-5897. doi:10.1073/pnas.0306588101.

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Alternativer Titel : Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design

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 Urheber:
Fedorov, Roman1, Autor           
Vasan, Ryan, Autor
Gosh, Dipak K., Autor
Schlichting, Ilme1, Autor           
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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 Zusammenfassung: The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested.

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Sprache(n): eng - English
 Datum: 2003-10-112004-02-032004-04-072004-04-20
 Publikationsstatus: Erschienen
 Seiten: 6
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Titel: Proceedings of the National Academy of Sciences of the United States of America
  Andere : Proc. Natl. Acad. Sci. U. S. A.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: National Academy of Sciences
Seiten: - Band / Heft: 101 (16) Artikelnummer: - Start- / Endseite: 5892 - 5897 Identifikator: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230